Blood coagulation is a process consisting of a complex interaction of various blood components, or factors, which eventually gives rise to a fibrin clot. Generally, the blood components which participate in what has been referred to as the coagulation "cascade" are proenzymes or zymogens, enzymatically inactive proteins, which are converted to proteolytic enzymes by the action of an activator, itself an activated clotting factor. Coagulation factors that have undergone such a conversion and generally referred to as "active factors", and are designated by the addition of the letter "a" to the name of the coagulation factor (e.g. fVIIa).
Activated factor X (fXa) is required to convert prothrombin to thrombin, which then converts fibrinogen to fibrin as a final stage in forming a fibrin clot. There are two systems, or pathways that promote the activation of factor X. The "intrinsic pathway" refers to those reactions that lead to thrombin formation through utilisation of factors present only in plasma. A series of protease-mediated activations ultimately generates factor IXa, which, in conjunction with factor Villa, cleaves factor X into Xa. An identical proteolysis is effected by fVIIa and its cofactor TF in the "extrinsic pathway" of blood coagulation. TF is a membrane bound protein and does not normally circulate in plasma. Upon vessel disruption, however, it is exposed and forms a complex with fVIIa to catalyse factor X activation or factor IX activation in the presence of Ca.sup.2+ and phospholipid (Nemerson and Gentry, Biochemistry 25:4020-4033 (1986)). While the relative importance of the two coagulation pathways in hemostasis is unclear, in recent years fVIIa and TF have been found to play a pivotal role in the initiation and regulation of blood coagulation.
FVII is a trace plasma glycoprotein that circulates in blood as a single-chain zymogen. The zymogen is catalytically inactive (Williams et al., J. Biol. Chem. 264:7536-7543 (1989); Rao et al., Proc. Natl. Acad. Sci. USA. 85:6687-6691 (1988)). Single-chain fVII may be converted to two-chain fVIIa by factor Xa, factor XIIa, factor IXa, fVIIa or thrombin in vitro. Factor Xa is believed to be the major physiological activator of fVII. Like several other plasma proteins involved in hemostasis, fVII is dependent on vitamin K for its activity, which is required for the gamma-carboxylation of multiple glutamic acid residues that are clustered in the amino terminus of the protein. These gamma-carboxylated glutamic acids are required for the metal-associated interaction of fVII with phospholipids.
The conversion of zymogen fVII into the activated two-chain molecule occurs by cleavage of an internal Arg152-Ile153 peptide bond (Hagen et al., Proc. Natl. Acad. Sci. USA 83: 2412-2416 (1986); Thim et al., Biochemistry 27:7785-7793 (1988)). In the presence of TF, phospholipids and calcium ions, the two-chain fVIIa rapidly activates factor X or factor IX by limited proteolysis.
It is often desirable to selectively block or inhibit the coagulation cascade in a patient. Anticoagulants such as heparin, coumarin, derivatives of coumarin, indandione derivatives, thrombin inhibitors, factor Xa inhibitors, modified fVII or other agents may be used.
Inhibition of coagulation is beneficial in a number of diseased states, for example 25 during kidney dialysis, or to treat deep vein thrombosis, disseminated intravascular coagulation (DIC) and a host of other medical disorders. For example, heparin treatment or extracorporeal treatment with citrate ions (U.S. Pat. No. 4,500,309) may be used in dialysis to prevent coagulation during the course of treatment. Heparin is also used in preventing deep vein thrombosis in patients undergoing surgery. Treatment with heparin and other anticoagulants may, however, have undesirable side effects. Available anticoagulants generally act throughout the body, rather than acting specifically at the site of injury, i.e. the site at which the coagulation cascade is active. Heparin, for example, may cause severe bleedings. Furthermore, with a half-life of approximately 80 minutes, heparin is rapidly cleared from the blood, necessitating frequent administrating. Because heparin acts as a cofactor for antithrombin III (AT III), and AT III is rapidly depleted in DIC treatment, it is often difficult to maintain the proper heparin dosage, necessitating continuous monitoring of AT III and heparin levels. Heparin is also ineffective if AT III depletion is extreme. Further, prolonged use of heparin may also increase platelet aggregation and reduce platelet count, and has been implicated in the development of osteoporosis. Indandione derivatives may also have toxic side effects.
Other known anticoagulants comprise thrombin and factor Xa inhibitors derived from bloodsucking organisms. Antithrombins, hirudin, hirulog and hirugen are recombinant proteins or peptides derived from the leach Hirudo medicinalis, whereas the factor Xa inhibitor antistatin and the recombinant derivative rTAP are tick-derived proteins. Inhibitors of platelet aggregation such as monoclonal antibodies or synthetic peptides, which interfere with the platelet receptor GPIIb/IIa are also effective as anticoagulants.
Bleeding complications are observed as an undesired major disadvantage of anti-thrombin, anti-factor Xa, as well as anti-platelet reagents. This side effect is strongly decreased or absent with inhibitors of the fVIIa/TF activity. Such anticoagulants comprise the physiological inhibitor TFPI (tissue factor pathway inhibitor) and modified fVII (fVIIai), which is fVIIa modified in such a way that it is catalytically inactive but still binds to TF and competes with active fVIIa.
In addition to the anticoagulants briefly described above, several naturally occurring proteins have been found to have anticoagulant activity. For example, Reutelingsperger (U.S. Pat. No. 4,736,018) isolated anticoagulant proteins from bovine aorta and human umbilical vein arteries. Maki et al. (U.S. Pat. No. 4,732,891) disclose human placenta-derived anticoagulant proteins. In addition, AT III has been proposed as a therapeutic anticoagulant (Schipper et al., Lancet 1 (8069): 854-856 (1978); Jordan, U.S. Pat. No. 4,386,025; Bock et al., U.S. Pat. No. 4,517,294).
Proliferation of smooth muscle cells (SMCs) in the vessel wall is an important event in the formation of vascular lesions in atherosclerosis, after vascular reconstruction or in response to other vascular injury. For example, treatment of atherosclerosis frequently includes the clearing of blocked vessels by angioplasty, endarterectomy or reduction atherectomy, or by bypass grafting, surgical procedures in which atherosclerotic plaques are compressed or removed through catheterization (angioplasty), stripped away from the arterial wall through an incision (endarterectomy) or bypassed with natural or synthetic grafts. These procedures remove the vascular endothelium, disturb the underlying intimal layer, and result in the death of medial SMCs. This injury is followed by medial SMC roliferation and migration into the intima, which typically occurs within the first few weeks nd up to six months after injury and stops when the overlying endothelial cell layer is re-stablished. In humans, these lesions are composed of about 20% cells and 80% extracellular matrix.
In about 30% or more of patients treated by angioplasty, endarterectomy or bypass grafts, thrombosis and/or SMC proliferation in the intima causes re-occlusion of the vessel and consequent failure of the reconstructive surgery. This closure of the vessel subsequent to surgery is known as restenosis.
Modified FVIIa (FVIIai) has been shown to effectively suppress the restenosis process possibly as a result of a decreased procoagulant activity and thrombin generation initially after treatment of the constricted vessel.
For long term prophylactic treatment and increased compliance it would be desirable to have access to low-molecular-weight compounds which may be administered via a route other than intravenously and which have an inhibitory effect on fVIIa-TF activity similar to that of fVIIai. Related patent applications covering low-molecular-weight compounds which down-regulate FVIIa-TF activity include;
JP 07242538 which describes naphthalene derivatives with tissue factor antagonist activity, PA1 U.S. Pat. No. 5,639,739 which describes peptide analogues derived from imidazolyl-boronic acid inhibiting FVIIa. Patent applications covering compounds based on peptides from TFPI, PA1 JP 6157591 describes compounds based on TFPI-derived peptides with FVIIa-TF antagonist activity, PA1 WO 90/03390, WO 95/00541, WO 96/18653, and EP 500 800 describe compounds based on FVIIa-derived peptides with FVIIa-TF antagonist activity, PA1 U.S. Pat. No. 4,315,766 describes 5-substituted 4H-3,1-Benzoxazinone structures with meta/para substituted aryls in the 2-position. The derivatives have been investigated for activity as herbicides; PA1 WO 96/07648 describes substituted amino groups in the 2-position for treatment of inflammation processes; PA1 U.S. Pat. No. 4,745,116 describes 4H-3,1-benzoxazinone structures having substituted oxygen groups in the 2-position; PA1 WO 91/15487 describes 5-substituted 4H-3,1-benzoxazinone structures having substituted alkyl groups in the 2-position. PA1 Bioorg. Med. Chem.Lett. (6) 679, 1996 mentions examples of structures having the 4H-3,1-benzoxazin skeleton, e.g. C1r inhibitors; PA1 Bioorg. Med. Chem. Lett. (7) 2527, 1997 describes structures having the 4H-3,1-benzoxazin skeleton which are inhibitors of serine proteases of the chymotrypsin family, the serinprotease inhibitors being 2-alpha-aminoalkyl derivatives; PA1 J. Med. Chem. (32) 265 1989 1997 describes structures having the 4H-3,1-benzoxazin skeleton which are plasma lipid lowering agents; PA1 J. Med. Chem. (33) 464 1990 describes structures having the 4H-3,1-benzoxazin skeleton which are inhibitors of human leukocyte elastase. PA1 CA 1,092,118 describe 2-phenylsubstituted quinazolin-4-one derivatives which are antiallergic agents; PA1 BE 862,201 describe 2-phenylsubstituted quinazolin-4-one derivatives which are 15 antiallergic agents; PA1 DE 2,654,215 describe 2-phenylsubstituted quinazolin-4-one derivatives which are antiallergic agents. PA1 Egypt. J. Pharm. Sci., 35(1-6), 1-20, 1994 describes 2-thienyl-benzoxazin-4-one derivatives which have been screened for antiinflammatory activity. PA1 DE 3,000,309 describes 2-haloalkenyl-benzoxazin-4-thione derivatives with herbicidal effect. PA1 J. Heterocycl. Chem. 28(8), 2005-12,1991 describes 2-arylsubstituted benzoxazin-4-one derivatives with calcium antagonistic effect. PA1 JP 55147279 describes 2-pyridylsubstituted quinazolin-4-one derivatives with antidepressant and inflammation inhibting effect. PA1 treatment of coagulation-related diseases; PA1 treatment of mammals suffering from deep vein thrombosis, pulmonary embolism, stroke, disseminated intravascular coagulation (DIC), vascular restenosis, platelet deposition and associated disorders, and myocardial infarction; PA1 prophylactic treatment of mammals with atherosclerotic vessels at risk for thrombosis; modulating and normalising an impaired haemostatic balance in a mammal; PA1 inhibiting blood coagulation in a mammal, or inhibiting clotting activity in a mammal, or inhibiting deposition of fibrin in a mammal, or inhibiting fibrin in a mammal. PA1 X and Y is independently O, S or NH; PA1 R.sup.1 and R.sup.2 independently are PA1 R.sup.3 is aryl or heteroaryl, each optionally substituted with one or more PA1 R.sup.4 is C.sub.1-4 -alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.3-6 cycloalkyl, or phenyl; PA1 5,8-Dichloro-2-(2-fluoro-phenyl)-4H-3,1-benzoxazin-4-one (1) PA1 6-Methyl-2-thiophen-2-yl-4H-3,1-benzoxazin-4-one (2) PA1 (2,6-Dichloro-phenyl)-6-methyl-4H-3,1-benzoxazin-4-one (3) PA1 6-Methyl-2-(2-trifluoromethoxy-phenyl)-4H-3,1-benzoxazin-4-one (4) PA1 (2,6-Difluoro-phenyl)-6-methyl-4H-3,1-benzoxazin4-one (5) PA1 (2,6-Dimethoxy-phenyl)-6-methyl-4H-3,1-]benzoxazin4-one (6) PA1 (3-Bromo-thiophen-2-yl)-6-methyl-4H-3,1-benzoxazin-4-one (7) PA1 (2,3-Dichloro-phenyl)-6-methyl-4H-3,1-benzoxazin-4-one (8) PA1 2-(2,6-Difluoro-phenyl)-6-methoxy-benzo[d][1,3]oxazin-4-one PA1 2-(2-Fluoro-phenyl)-6-methoxy-benz[d][1,3]oxazin-4-one PA1 2-(2,6-Difluoro-phenyl)-7-trifluoromethyl-benzo[d][1,3]oxazin-4-one PA1 6,7-Difluoro-2-(2-fluoro-phenyl)-benzo[d][1,3]oxazin-4-one PA1 6,7-Difluoro-2-thiophen-2-yl-benzo[d][1,3]oxazin-4-one PA1 6,7-Difluoro-2-furan-2-yl-benzo[d][1,3]oxazin-4-one PA1 2-(2,6-Difluoro-phenyl)-4-oxo-4H-benzo[d][1,3]oxazine-5-carboxylic acid methyl ester PA1 2-(2-Fluoro-phenyl)-4-oxo-4H-benzo[d][1,3]oxazine-5-carboxylic acid methyl ester PA1 4-Oxo-2-thiophen-2-yl-4H-benzo[d][1,31oxazine-5-carboxylic acid methyl ester PA1 2-Furan-2-yl-4-oxo-4H-benzo[d][1,3]oxazine-5-carboxylic acid methyl ester PA1 2-(2-Methoxy-phenyl)-6-nitro-benzo[d][1,3]oxazin-4-one PA1 2-(2-Methoxy-phenyl)-5-methyl-benzo[d][1,3]oxazin-4-one PA1 2-(2-Methoxy-phenyl)-5-nitro-benzo[d][1,3]oxazin-4-one PA1 6-Nitro-2-(2-nitro-phenyl)-benzo[d][1,3]oxazin-4-one PA1 6-Nitro-2-o-tolyl-benzo[d][1,3]oxazin-4-one PA1 5-Nitro-2-(2-nitro-phenyl)-benzo[d][1,3]oxazin-4-one PA1 5-Nitro-2-(2-nitro-phenyl)-benzo[d][1,3]oxazin-4-one PA1 2-(2-Chloro-pyridin-3-yl)-6-nitro-benzo[d][1,3]oxazin-4-one PA1 2-(2-Chloro-pyridin-3-yl)-5-methyl-benzo[d][1,3]oxazin-4-one PA1 2-(2-Chloro-pyridin-3-yl)-5-nitro-benzo[d][1,3]oxazin-4-one PA1 2-(2,3-Difluoro-phenyl)-6-nitro-benzo[d][1,3]oxazin-4-one PA1 2-(2,3-Difluoro-phenyl)-5-methyl-benzo[d][1,3]oxazin-4-one PA1 2-(2,3-Difluoro-phenyl)-5-nitro-benzo[d][1,3]oxazin-4-one PA1 Acetic acid 2-(6-nitro-4-oxo-4H-benzo[d]1,3)oxazin-2-yl)-phenyl ester PA1 Acetic acid 2-(5-methyl-4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-phenyl ester PA1 Acetic acid 2-(5-nitro-4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-phenyl ester PA1 2-(2,6-Difluoro-phenyl)-6-trifluoromethyl-benzo[d][1,3]oxazin-4-one PA1 2-(2-Fluoro-phenyl)-6-trifluoromethyl-benzo[d][1,3]oxazin-4-one PA1 2-Thiophen-2-yl-6-trifluoromethyl-benzo[d][ 1,3]oxazin-4-one PA1 2-(2,6-Difluoro-phenyl)-5-trifluoromethyl-benzo[d][1,3]oxazin-4-one PA1 2-(2-Fluoro-phenyl)-5-trifluoromethyl-benzo[d][1,3]oxazin-4-one PA1 2-Thiophen-2-yl-5-trifluoromethyl-benzo[d][1,3]oxazin-4-one PA1 2-(2,6-Difluoro-phenyl)-8-trifluoromethyl-benzo[d][1,3]oxazin-4-one PA1 2-(2-Fluoro-phenyl)-8-trifluoromethyl-benzo[d][1,3]oxazin-4-one PA1 2-Furan-2-yl-8-trifluoromethyl-benzo[d][1,3]oxazin-4-one PA1 2-(2-Fluoro-phenyl)-4-oxo-4H-benzo[d][1,3]oxazine-5-carboxylic acid ethyl ester PA1 2-(2,6-Difluoro-phenyl)-7-fluoro-benzo[d][1,3]oxazin-4-one PA1 5-Nitro-2-(5-nitro-furan-2-yl)-benzo[d][1,3]oxazin-4-one PA1 2-(2,3-Dichloro-phenyl)-6,7-difluoro-benzo[d][1,3]oxazin-4-one PA1 6,7-Difluoro-2-(2-trifluoromethoxy-phenyl)-benzo[d][1,3]oxazin-4-one PA1 2-(2,3-Difluoro-phenyl)-6,7-difluoro-benzo[d][1,3]oxazin-4-one PA1 6, 7-Difluoro-2-(2-methoxy-phenyl)-benzo[d][1,3]oxazin-4-one PA1 2-(2-Chloro-pyridin-3-yl)-6,7-difluoro-benzo[d][1,3]oxazin-4-one PA1 2-(2,6-Difluoro-phenyl)-6-nitro-benzo[d][1,3]oxazin-4-one (9) PA1 6-Acetamido-(2,6-difluoro-phenyl)-benzo[d][1,3]oxazin-4-one (10) PA1 2-(2,6-Difluoro-phenyl)-5-methyl-benzo[d][1,3]oxazin-4-one (11) PA1 2-(2,6-Difluoro-phenyl)-7-nitro-benzo[d][1,3]oxazin-4-one (12) PA1 2-(2,6-Difluoro-phenyl)-5-nitro-benzo[d][1,3]oxazin-4-one (13) PA1 5-Chloro-2-(2,6-difluoro-phenyl)-benzo[d][1,3]oxazin-4-one (14) PA1 6-Amino-2-(2,6-difluoro-phenyl)-benzo[d][1,3]oxazin-4-one (15) PA1 2-(2,6-Difluoro-phenyl)-8-hydroxy-benzo[d][1,3]oxazin-4-one (16) PA1 5,8-Dichloro-2-(2,6-difluoro-phenyl)-benzo[d][1,3]oxazin-4-one (17) PA1 5-Amino-2-(2,6-difluoro-phenyl)-benzo(d][1,3]oxazin-4-one (18) PA1 2-(2,6-Difluoro-phenyl)-6,7-difluoro-benzo[d][1,3]oxazin-4-one (19) PA1 7-Amino-2-(2,6-difluoro-phenyl)-benzo[d][1,3]oxazin-4-one (20) PA1 2-(2,5-Dimethyl-benzofuran-7-yl)-4H-3,1-benzoxazin-4-one PA1 2-(3-Bromo-phenyl)-4H-3,1-benzoxazin-4-one PA1 2-(3-Bromo-phenyl)-7-chloro-4H-3,1-benzoxazin-4-one PA1 2-(2,4-Dichloro-phenyl)-4H-3,1-benzoxazin-4-one PA1 2-m-Tolyl-4H-3,1-benzoxazin-4-one PA1 2-(2-Fluoro-phenyl)-6-methyl-3,1-benzoxazin-4-one PA1 2-(4-tert-Butyl-phenyl)-7-chloro-4H-3,1-benzoxazin-4-one PA1 Naphthalene-2-sulfinic acid [2-(4-oxo-4H-3,1-benzoxazin-2-yl)-phenyl]-amide PA1 2-(4-Chloro-3-nitro-phenyl)-6,7-dimethoxy-4H-3,1-benzoxazin-4-one PA1 2-(5-Chloro-2-methoxy-phenyl)-4H-3,1-benzoxazin-4-one PA1 6-Bromo-2-(5-chloro-2-methoxy-phenyl)-4H-3,1-benzoxazin-4-one PA1 2-(3,4-Dichloro-phenyl)-6,7-dimethoxy-4H-3,1-benzoxazin-4-one PA1 2-(3,4-Dimethyl-phenyl)-4H-3,1-benzoxazin-4-one PA1 7-Chloro-2-(4-methyl-3-nitro-phenyl)-4H-3,1-benzoxazin-4-one PA1 6,7-Dimethoxy-2-p-tolyl-4H-3,1-benzoxazin-4-one PA1 2-phenyl-4H-3,1-benzoxazin-4-one PA1 6,7,8-Trimethoxy-2-(3-trifluoromethyl-phenyl)-4H-3,1-benzoxazin-4-one PA1 6,7-Dimethoxy-2-[2-(4-methoxy-phenoxy)-5-nitro-phenyl]-[4H-3,1-benzoxazin-4 -one PA1 5-Chloro-2-[2-(4-methoxy-phenoxy)-5-nitro-phenyl]-4H-3,1-benzoxazin-4-one PA1 2-(4-tert-Butyl-phenyl)-7-chloro-4H-3,1-benzoxazin-4-one PA1 7-Chloro-2-m-tolyl-4H-3,1-benzoxazin-4-one PA1 6,7-Dimethoxy-2-(5-methyl-2-nitro-phenyl)-4H-3,1-benzoxazin-4-one PA1 7-Chloro-2-(4-chloro-3-nitro-phenyl)-4H-3,1-benzoxazin-4-one PA1 2-(3,4-Dimethyl-phenyl)-6,7-dimethoxy-4H-3,1-benzoxazin-4-one PA1 7-Chloro-2-[4-(5-ethyl-pyridin-2-yl)-phenyl]-4H-3,1-benzoxazin-4-one PA1 2-(4-Chloro-3-nitrophenyl)-6,7,8-trimethoxy-4H-3,1-benzoxazin-4-one PA1 2-(2,6-Difluorophenyl)-5-fluoro-4H-3,1-benzoxazin-4-one PA1 2-(2-Fluorophenyl)-4H-3,1-benzoxazin-4-one PA1 5-Chloro-2-(3-trifluoromethylphenyl)-4H-3,1-benzoxazin-4-one PA1 2-(3,4-Dichloro-phenyl)-6-nitro-4H-3,1-benzoxazin-4-one PA1 2-(2-Chloro-6-fluorophenyl)-5-fluoro-3,1-benzoxazin-4-one PA1 7-Chloro-2-(2-fluorophenyl)-3,1-benzoxazin-4-one PA1 2-(2-Chloro-6-fluorophenyl)-6-methyl-4H-3,1-benzoxazin-4-one PA1 2(2-(4-Fluorophenylsulfonyl)amidophenyl)-4H-3,1-benzoxazin-4-one PA1 2-(2-Bromo-5-methoxy-phenyl)-4H-3,1-benzoxazin-4-one PA1 2-(2-Chloromethyl-phenyl)-4H-3,1-benzoxazin-4-one PA1 2-(4-tert-Butyl-phenyl)-6,8-dimethyl-4H-3,1-benzoxazin-4-one PA1 2-(2-Chloro-phenyl)-6-methyl-4H-3,1-benzoxazin-4-one PA1 7-Chloro-2-(3-chloromethyl-phenyl)-4H-3,1-benzoxazin-4-one PA1 2-(2-Chloro-phenyl)-6-iodo-4H-3,1-benzoxazin-4-one PA1 7-Chloro-2-(2-chloro-5-nitro-phenyl)-4H-3,1-benzoxazin-4-one PA1 2-(2-Bromo-phenyl)-6-chloro-4H-3,1-benzoxazin-4-one PA1 6,7-Dimethoxy-2-(3-nitro-phenyl)-4H-3,1-benzoxazin-4-one PA1 2-(3-Nitro-phenyl)4H-3,1-benzoxazin-4-one PA1 7-chloro-2-(2,4-dichlorophenyl)-4H-3,1-benzoxazin-4-on PA1 2-(2,4-Dichloro-phenyl)-6-iodo-4H-3,1-benzoxazin-4-one PA1 6-Bromo-2-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-4H-3,1-benzoxazin-4-one PA1 6-(6,7-Dimethoxy-4-oxo-4H-3,1-benzoxazin-2-yl)-pyridine-2-carboxylic acid methyl ester PA1 6,7-Dimethoxy-2-pyridin-4-yl-4H-3,1-benzoxazin-4-one PA1 6-Bromo-2-pyridin-4-yl-4H-3,1-benzoxazin-4-one PA1 5-Fluoro-2-(2-phenoxy-pyridin-3-yl)-4H-3,1-benzoxazin-4-one PA1 6,7,8-Trimethoxy-2-(2-phenoxy-pyridin-3-yl)-4H-3,1-benzoxazin-4-one PA1 2-(3-Chloro-5-trifluoromethyl-pyridin-2-yl)-6,7-dimethoxy-4H-3,1-benzoxazin -4-one PA1 2-Thiophen-2-yl-4H-3,1-benzoxazin-4-one PA1 6,7,8-Trimethoxy-2-(5-nitro-furan-2-yl)-4H-3,1-benzoxazin-4-one PA1 6-Methyl-2-(5-nitro-furan-2-yl)-4H-3,1-benzoxazin-4-one PA1 2-(2,4-Dichloro-phenyl)-6-nitro-benzo[d][1,3]oxazin-4-one) PA1 6,8-Dibromo-2-(2-fluoro-phenyl)-benzo[d][1,3]oxazin-4-one PA1 7-Chloro-2-(2-chloromethyl-phenyl)-4H-3,1-benzoxazin-4-one PA1 5,8-Dichloro-2-(2-fluoro-phenyl)-4H-3,1-benzoxazin-4-one PA1 6-Methyl-2-thiophen-2-yl-4H-3,1-benzoxazin-4-one PA1 2-(2,6-Dichloro-phenyl)-6-methyl-4H-3,1-benzoxazin-4-one PA1 6-Methyl-2-(2-trifluoromethoxy-phenyl)-4H-3,1-benzoxazin-4-one PA1 2-(2,6-Difluoro-phenyl)-6-methyl-4H-3,1-benzoxazin-4-one PA1 2-(2,6-Dimethoxy-phenyl)-6-methyl-4H-3,1-]benzoxazin-4-one PA1 2-(3-Bromo-thiophen-2-yl)-6-methyl-4H-3,1-benzoxazin-4-one PA1 2-(2,3-Dichloro-phenyl)-6-methyl-4H-3,1-benzoxazin-4-one PA1 2-(2,6-Difluoro-phenyl)-6-methoxy-benzo[d][1,3]oxazin-4-one PA1 2-(2-Fluoro-phenyl)-6-methoxy-benzo[d][1,3]oxazin-4-one PA1 2-(2,6-Difluoro-phenyl)-7-trifluoromethyl-benzo[d][1,3]oxazin-4-one PA1 6,7-Difluoro-2-(2-fluoro-phenyl)-benzo[d][1,3]oxazin-4-one PA1 6,7-Difluoro-2-thiophen-2-yl-benzo[d][1,3]oxazin-4-one PA1 6,7-Difluoro-2-furan-2-yl-benzo[d][1,3]oxazin-4-one PA1 2-(2,6-Difluoro-phenyl)-4-oxo-4H-benzo[d][1,3]oxazine-5-carboxylic acid methyl ester PA1 2-(2-Fluoro-phenyl)-4-oxo-4H-benzo[d][1,3]oxazine-5-carboxylic acid methyl ester PA1 4-Oxo-2-thiophen-2-yl-4H-benzo[d][1,3]oxazine-5-carboxylic acid methyl ester PA1 2-Furan-2-yl-4-oxo-4H-benzo[d][1,3]oxazine-5-carboxylic acid methyl ester PA1 2-(2-Methoxy-phenyl)-6-nitro-benzo[d][1,3]oxazin-4-one PA1 2-(2-Methoxy-phenyl)-5-methyl-benzo[d][1,3]oxazin-4-one PA1 2-(2-Methoxy-phenyl)-5-nitro-benzo[d][1,3]oxazin-4-one PA1 6-Nitro-2-(2-nitro-phenyl)-benzo[d][1,3]oxazin-4-one PA1 6-Nitro-2-o-tolyl-benzo[d][1,3]oxazin-4-one PA1 5-Nitro-2-(2-nitro-phenyl)-benzo[d][1,3]oxazin-4-one PA1 5-Nitro-2-(2-nitro-phenyl)-benzo[d][1,3]oxazin-4-one PA1 2-(2-Chloro-pyridin-3-yl)-6-nitro-benzo[d][1,3]oxazin-4-one PA1 2-(2-Chloro-pyridin-3-yl)-5-methyl-benzo[d][1,3]oxazin-4-one PA1 2-(2-Chloro-pyridin-3-yl)-5-nitro-benzo[d][1,3]oxazin-4-one PA1 2-(2,3-Difluoro-phenyl)-6-nitro-benzo[d][1,3]oxazin-4-one PA1 2-(2,3-Difluoro-phenyl)-5-methyl-benzo[d][1,3]oxazin-4-one PA1 2-(2,3-Difluoro-phenyl)-5-nitro-benzo[d][1,3]oxazin-4-one PA1 Acetic acid 2-(6-nitro-4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-phenyl ester PA1 Acetic acid 2-(5-methyl-4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-phenyl ester PA1 Acetic acid 2-(5-nitro4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-phenyl ester PA1 2-(2,6-Difluoro-phenyl)-6-trifluoromethyl-benzo[d][1,3]oxazin-4-one PA1 2-(2-Fluoro-phenyl)-6-trifluoromethyl-benzo[d][1,3]oxazin-4-one PA1 2-Thiophen-2-yl-6-trifluoromethyl-benzo[d][1,3)oxazin-4-one PA1 2-(2,6-Difluoro-phenyl)-5-trifluoromethyl-benzo[d][1,3]oxazin-4-one PA1 2-(2-Fluoro-phenyl)-5-trifluoromethyl-benzo[d][1,3]oxazin-4-one PA1 2-Thiophen-2-yl-5-trifluoromethyl-benzo[d][1,3]oxazin-4-one PA1 2-(2,6-Difluoro-phenyl)-8-trifluoromethyl-benzo[d][1,3]oxazin-4-one PA1 2-(2-Fluoro-phenyl)-8-trifluoromethyl-benzo[d][1,3]oxazin-4-one PA1 2-Furan-2-yl-8-trifluoromethyl-benzo[d][1,3]oxazin-4-one PA1 2-(2-Fluoro-phenyl)-4-oxo-4H-benzo[d][1,3]oxazine-5-carboxylic acid ethyl ester PA1 2-(2,6-Difluoro-phenyl)-7-fluoro-benzo[d][1,3]oxazin-4-one PA1 5-Nitro-2-(5-nitro-furan-2-yl)-benzo[d][1,3]oxazin-4-one PA1 2-(2,3-Dichloro-phenyl)-6,7-difluoro-benzo[d][1,3]oxazin-4-one PA1 6,7-Difluoro-2-(2-trifluoromethoxy-phenyl)-benzo[d][1,3]oxazin-4-one PA1 2-(2,3-Difluoro-phenyl)-6,7-difluoro-benzo[d][1,3]oxazin-4-one PA1 6,7-Difluoro-2-(2-methoxy-phenyl)-benzo[d][1,3]oxazin-4-one PA1 2-(2-Chloro-pyridin-3-yl)-6,7-difluoro-benzo[d][1,3]oxazin-4-one PA1 2-(2,6-Difluoro-phenyl)-6-nitro-benzo[d][1,3]oxazin-4-one PA1 6-Acetamido-(2,6-difluoro-phenyl)-benzo[d][1,3]oxazin-4-one PA1 2-(2,6-Difluoro-phenyl)-5-methyl-benzo[d][1,3]oxazin-4-one PA1 2-(2,6-Difluor-phenyl)-7-nitro-benzo[d][1,3]oxazin-4-one PA1 2-(2,6-Difluoro-phenyl)-5-nitro-benzo[d][1,3]oxazin-4-one PA1 5-Chloro-2-(2,6-difluoro-phenyl)-benzo[d][1,3]oxazin-4-one PA1 6-Amino-2-(2,6-difluoro-phenyl)-benzo[d][1,3]oxazin-4-one PA1 2-(2,6-Difluoro-phenyl)-8-hydroxy-benzo[d][1,3]oxazin-4-one PA1 5,8-Dichloro-2-(2,6-difluoro-phenyl)-benzo[d][1,3]oxazin-4-one PA1 5-Amino-2-(2,6-difluoro-phenyl)-benzo[d][1,3]oxazin-4-one PA1 2-(2,6-Difluoro-phenyl)-6,7-difluoro-benzo[d][1,3]oxazin-4-one PA1 7-Amino-2-(2,6-difluoro-phenyl)-benzo[d][1,3]oxazin-4-one PA1 A) reacting a compound of formula II ##STR5## PA1 with a compound of the formula R.sup.3 COL; R.sup.1, R.sup.2, R.sup.3, X, and Y having the meanings described above, L being a good leaving group such as halogen, sulfate, or acyl group. PA1 B) PA1 C) reacting a compound of the formula III ##STR9## PA1 with an agent capable of introducing ring closure to form a structure of the formula I. PA1 D) reaction of a structure of the formula IV ##STR10## PA1 in which R.sup.1, R.sup.2, and R.sup.3 has the meaning described above and R.sup.4 is an C.sub.1-8 alkyl group with an agent capable of introducing ring closure like conc. H.sub.2 SO.sub.4 or similar agents which can introduce combined hydrolysis and ring closure under absorption of water. PA1 E. P. Papadopoulos and C. D. Torres: Heterocycles 19 (6) 1039-1042, 1982; PA1 J. L. Gilmore et al:. Bioorganic and Medicinal Chemistry Letters 6 (6), 679-682, 1996; PA1 M Davies, R. J. Hook, Wen Yang Wu: J. Heterocyclic. Chem. 21 369-373, 1984; PA1 G. Hamprecht, B. Wuerzer: U.S. Pat. No. 4,315,766, 1982; PA1 2-(2,5-Dimethyl-benzofuran-7-yl)-4H-3,1-benzoxazin-4-one PA1 2-(3-Bromo-phenyl)-4H-3,1-benzoxazin-4-one PA1 2-(3-Bromo-phenyl)-7-chloro-4H-3,1-benzoxazin-4-one PA1 2-(2,4-Dichloro-phenyl)-4H-3,1-benzoxazin-4-one PA1 2-m-Tolyl-4H-3,1-benzoxazin-4-one PA1 2-(2-Fluoro-phenyl)-6-methyl-3,1-benzoxazin-4-one PA1 2-(4-tert-Butyl-phenyl)-7-chloro-4H-3,1-benzoxazin-4-one PA1 Naphthalene-2-sulfinic acid [2-(4-oxo-4H-3,1-benzoxazin-2-yl)-phenyl]-amide PA1 2-(4-Chloro-3-nitro-phenyl)-6,7-dimethoxy-4H-3,1-benzoxazin-4-one PA1 2-(5-Chloro-2-methoxy-phenyl)-4H-3,1-benzoxazin-4-one PA1 6-Bromo-2-(5-chloro-2-methoxy-phenyl)-4H-3,1-benzoxazin-4-one PA1 2-(3,4-Dichloro-phenyl)-6,7-dimethoxy-4H-3,1-benzoxazin-4-one PA1 2-(3,4-Dimethyl-phenyl)-4H-3,1-benzoxazin-4-one PA1 7-Chloro-2-(4-methyl-3-nitro-phenyl)-4H-3,1-benzoxazin-4-one PA1 6,7-Dimethoxy-2-p-tolyl-4H-3,1-benzoxazin-4-one PA1 2-phenyl-4H-3,1-benzoxazin-4-one PA1 6,7,8-Trimethoxy-2-(3-trifluoromethyl-phenyl)-4H-3,1-benzoxazin-4-one PA1 6,7-Dimethoxy-2-[2-(4-methoxy-phenoxy)-5-nitro-phenyl]-4H-3,1-benzoxazin-4- one PA1 5-Chloro-2-[2-(4-methoxy-phenoxy)-5-nitro-phenyl]-4H-3,1-benzoxazin-4-one PA1 2-(4-tert-Butyl-phenyl)-7-chloro-4H-3,1-benzoxazin-4-one PA1 7-Chloro-2-m-tolyl-4H-3,1-benzoxazin-4-one PA1 6,7-Dimethoxy-2-(5-methyl-2-nitro-phenyl)-4H-3,1-benzoxazin-4-one PA1 7-Chloro-2-(4-chloro-3-nitro-phenyl)-4H-3,1-benzoxazin-4-one PA1 2-(3,4-Dimethyl-phenyl)-6,7-dimethoxy-4H-3,1-benzoxazin-4-one PA1 7-Chloro-2-[4-(5-ethyl-pyridin-2-yl)-phenyl]-4H-3,1-benzoxazin-4-one PA1 2-(4-Chloro-3-nitrophenyl)-6,7,8-trimethoxy-4H-3,1-benzoxazin-4-one PA1 2-(2,6-Difluorophenyl)-5-fluoro-4H-3,1-benzoxazin-4-one PA1 2-(2-Fluorophenyl)-4H-3,1-benzoxazin-4-one PA1 5-Chloro-2-(3-trifluoromethylphenyl)-4H-3,1-benzoxazin-4-one PA1 2-(3,4-Dichloro-phenyl)-6-nitro-4H-3,1-benzoxazin-4-one PA1 2-(2-Chloro-6-fluorophenyl)-5-fluoro-3,1-benzoxazin-4-one PA1 7-Chloro-2-(2-fluorophenyl)-3,1-benzoxazin-4-one PA1 2-(2-Chloro-6-fluorophenyl)-6-methyl-4H-3,1-benzoxazin-4-one PA1 2-(2-(4-Fluorophenylsulfonyl)amidophenyl)-4H-3,1-benzoxazin-4-one PA1 2-(2-Bromo-5-methoxy-phenyl)-4H-3,1-benzoxazin-4-one PA1 2-(2-Chloromethyl-phenyl)-4H-3,1-benzoxazin-4-one PA1 2-(4-tert-Butyl-phenyl)-6,8-dimethyl-4H-3,1-benzoxazin-4-one PA1 2-(2-Chloro-phenyl)-6-methyl-4H-3,1-benzoxazin-4-one PA1 7-Chloro-2-(3-chloromethyl-phenyl)-4H-3,1-benzoxazin-4-one PA1 2-(2-Chloro-phenyl)-6-iodo-4H-3,1-benzoxazin-4-one PA1 7-Chloro-2-(2-chloro-5-nitro-phenyl)-4H-3,1-benzoxazin-4-one PA1 2-(2-Bromo-phenyl)-6-chloro-4H-3,1-benzoxazin-4-one PA1 6,7-Dimethoxy-2-(3-nitro-phenyl)-4H-3,1-benzoxazin-4-one PA1 2-(3-Nitro-phenyl)-4H-3,1-benzoxazin-4-one PA1 7-chloro-2-(2,4-dichlorophenyl)-4H-3,1-benzoxazin-4-one PA1 2-(2,4-Dichloro-phenyl)-6-iodo-4H-3,1-benzoxazin-4-one PA1 6-Bromo-2-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-4H-3,1-benzoxazin-4-one PA1 6-(6,7-Dimethoxy-4-oxo-4H-3,1-benzoxazin-2-yl)-pyridine-2-carboxylic acid methyl ester PA1 6,7-Dimethoxy-2-pyridin-4-yl-4H-3,1-benzoxazin-4-one PA1 6-Bromo-2-pyridin-4-yl-4H-3,1-benzoxazin-4-one PA1 5-Fluoro-2-(2-phenoxy-pyridin-3-yl)-4H-3,1-benzoxazin-4-one PA1 6,7,8-Trimethoxy-2-(2-phenoxy-pyridin-3-yl)-4H-3,1-benzoxazin-4-one PA1 2-(3-Chloro-5-trifluoromethyl-pyridin-2-yl)-6,7-dimethoxy-4H-3,1-benzoxazin -4-one PA1 2-Thiophen-2-yl-4H-3,1-benzoxazin-4-one PA1 6,7,8-Trimethoxy-2-(5-nitro-furan-2-yl)-4H-3,1-benzoxazin-4-one PA1 6-Methyl-2-(5-nitro-furan-2-yl)-4H-3,1-benzoxazin-4-one PA1 5,8-Dichloro-2-(2-fluoro-phenyl)-4H-3,1-benzoxazin-4-one PA1 6-Methyl-2-thiophen-2-yl-4H-3,1-benzoxazin-4-one PA1 2-(2,6-Dichloro-phenyl)-6-methyl-4H-3,1-benzoxazin-4-one PA1 6-Methyl-2-(2-trifluoromethoxy-phenyl)-4H-3,1-benzoxazin-4-one PA1 2-(2,6-Difluoro-phenyl)-6-methyl-4H-3,1-benzoxazin-4-one PA1 2-(2,6-Dimethoxy-phenyl)-6-methyl-4H-3,1-]benzoxazin-4-one PA1 2-(3-Bromo-thiophen-2-yl)-6-methyl-4H-3,1-benzoxazin-4-one PA1 2-(2,3-Dichloro-phenyl)-6-methyl-4H-3,1-benzoxazin-4-one PA1 2-(2,4-Dichloro-phenyl)-6-nitro-benzo[d][1,3]oxazin-4-one PA1 6,8-Dibromo-2-(2-fluoro-phenyl)-benzo[d][1,3]oxazin-4-one PA1 7-Chloro-2-(2-chloromethyl-phenyl)-4H-3,1-benzoxazin-4-one
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There is still a need in the art for improved compositions having anticoagulant activity which can be administered orally or otherwise non-intravenously at relatively low doses and not producing the undesirable side effects associated with traditional anticoagulant compositions. The present invention fulfills this need by providing anticoagulants that act specifically on fVIIa-TF at sites of injury, and further provides other related advantages such as its effect on the restenosis process. As compared to most other anticoagulants with an effect on the fVIIa-TF activity, the present invention has the advantage that it is a small synthetic molecule suitable for oral administration and for prophylactic treatment of atherosclerotic patients at risk for thrombosis.